CMA: Immune/Inflammatory Priming in Exacerbating Responses to GWVI Stressors: Implications for GWVI Treatments

CMA：免疫/炎症引发加剧对 GWVI 应激源的反应：对 GWVI 治疗的影响

• 批准号: 10291806
• 负责人: Saurabh Chatterjee
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291806
• 关键词: Affect; Animal Model; Antidotes; Attenuated; Autoantibodies; Autoimmune Diseases; Award; Biological Models; Biological Response Modifiers; Blood; Brain; Bromine; Butyrates; Cell Death; Chemical Exposure; Chemicals; Chemistry; Clinical; Collaborations; Complex; Coupled; Data; Development; Diagnosis; Disease; Endotoxemia; Endotoxins; Etiology; Event; Experimental Models; Exposure to; Fatigue; Female; Future; Generations; Genes; Genetic Polymorphism; Genetic Variation; Goals; Gulf War; Gulf War veteran; HMGB1 gene; Human; Hydroxybutyrates; Immune; Immune response; Immune system; Immunity; Immunologic Tests; Immunologics; Immunotherapeutic agent; Impaired cognition; Individual; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Insecticides; Interdisciplinary Study; Interleukin-1 beta; Intestines; Isoprostanes; Joints; Knock-out; Knockout Mice; Lead; Leptin; Link; Lipid Peroxides; Mediating; Mediator of activation protein; Medical center; Metagenomics; Microbiology; Molecular; Mood Disorders; Mus; Neurons; Neurosciences; Organ failure; Outcome Study; Oxidative Stress; Pain; Pathologic; Pathology; Pathway interactions; Pattern; Pattern recognition receptor; Penetration; Permethrin; Pesticides; Pharmacology; Phenotype; Plasma; Play; Probiotics; Proteins; Public Health Schools; Reaction; Receptor Activation; Receptor Cell; Research; Research Personnel; Research Project Grants; Rodent; Rodent Model; Role; Sampling; Science; Small Intestines; Stimulus; Stress; Symptoms; Synaptic plasticity; Testing; Therapeutic Effect; Therapeutic Studies; Toxic Environmental Substances; Toxin; Translating; Translations; Uranium; Vaccination; Vaccines; Veterans; Veterans Health Administration; Vision; Work; arm; attenuation; base; cohort; cytokine; design; dysbiosis; environmental stressor; experience; fluorophosphate; gastrointestinal; gut dysbiosis; gut microbiome; immune activation; inhibitor/antagonist; innovation; insight; interest; metabolomics; microbiome; microbiome alteration; mouse model; multidisciplinary; nerve gas; neuroinflammation; novel; novel therapeutic intervention; pre-clinical research; programs; psychological stressor; pyridostigmine; relating to nervous system; response; stressor; tissue degeneration; translational study

This Collaborative Merit Review Award for Research (I01) proposed in response to RFA BX-18-007 from the Veteran Health Administration is a joint effort by investigators from the JJ Peters VA Medical Center (Bronx, NY) Project 1, Arnold School of Public Health and Wm Jennings Bryan Dorn VA Medical Center (Columbia, SC) Project 2, Brain Science Center VA Medical Center (Minneapolis, MN) Project 3. We define a vision for an integrated and multidisciplinary program of preclinical research projects all linked by the ultimate goal to better characterize the mechanism of persistent and aberrant immunological activity in Gulf War Veteran Illnesses (GWVI) by developing experimental model systems, with the ultimate goal of developing novel therapeutic interventions. Gulf War Veterans’ Illnesses is a multifaceted disorder characterized by a range of symptoms including cognitive impairment, fatigue, pain, mood disorders, among others. Recent evidence suggests that the onset and progression of these symptoms may be the result of disequilibrium in these subjects’ immune systems. During deployment GWV were exposed to a unique variety of toxic agents that were specific to the Gulf War theatre, such as pyridostigmine bromine (PB), diisopropyl fluorophosphates (DFP), permethrin, and depleted uranium which current evidence indicates lowered thresholds to immunological responses and resulted in the persistent and heightened activity of certain arms of the immune system; a phenomenon best described as “immunological priming”. In addition, they received more than 20 vaccines that could have overloaded the immune system. In support of these considerations, subjects with GWVI often have shown pathological signatures in common with autoimmune disorders and generalized inflammatory disorders, such as increased plasma concentrations of pro-inflammatory cytokines, unspecific tissue degeneration, and organ failure. Based on this concept, the three proposed collaborative research projects were designed to better understand how primed immune systems may contribute to GWVI- type phenotypes by exploring how multiple GWI conditions recapitulated in animal models may synergize and eventually provide new mechanistic evidence for translation studies. For example, Project 2 was designed to understand how GW toxin induced gut inflammasome activation causes gut dysbiosis and may lead to persistent or heightened immune-inflammatory responses and GWVI symptoms. As the goal of Project 3 is designed the hypothesis that lack of specific immunity leads to vaccine-induced inflammatory reaction in the brain, Project 2 will collaborate with project 3 to test the contribution of inflammasome priming and genetic diversity to gut dysbiosis and persistent immunological responses. Similarly, Project 1, which is designed to test how immunological priming may heighten inflammatory responses to psychological stressors, will collaborate with project 2 and project 3 by exploring how the NLRP3 inflammasome may contribute to heightened inflammation induced by gut dysbiosis or HLA polymorphisms, respectively. The outcome of these studies is of great interest not only because this will establish a novel link between inflammasome priming, genetic diversity and gut-dysbiosis toxemic response, but it will also provide insight to test novel therapeutic approaches that target the persistent activation of the immune system, either using immunotherapeutic approaches against vaccine toxins, probiotics to attenuate gut dysbiosis. Our proposed studies are innovative in terms of their scope, since it will fill the fundamental gaps needed for future translational studies. Most importantly our multiscale technological innovative approaches, which include knockout murine models of GWVI, including for the HLA and NLRP3 proteins, will enable our interdisciplinary research team with outstanding expertise in neuroscience, pharmacology, microbiology, chemistry to thoroughly investigate the molecular mechanisms underlying the etiology of GWVI.

该协作性研究研究奖（I01）是针对RFA BX-18-007提出的 资深卫生管理局是JJ Peters VA医疗中心（Bronx，Bronx， 纽约州Arnold公共卫生学院和WM Jennings Bryan Dorn VA医疗中心（哥伦比亚，哥伦比亚， SC）项目2，脑科学中心VA医疗中心（明尼苏达州明尼阿波利斯）项目3。我们定义了一个愿景 临床前研究项目的综合和多学科计划，所有这些都以最终目标联系在一起 更好地表征海湾退伍军人的持续性和异常免疫活动的机制 通过开发实验模型系统的疾病（GWVI），其最终目标是开发新颖 治疗干预措施。海湾战争退伍军人的病是一种多方面的疾病，其特征是一系列 症状包括认知障碍，疲劳，疼痛，情绪障碍等。最近的证据 表明这些症状的发作和进展可能是这些症状的结果 受试者的免疫系统。在部署期间，GWV暴露于独特的有毒药物中 特定于海湾战争剧院，例如吡啶斯汀溴（PB），二异丙基氟磷酸盐 （DFP），苄氯菊酯和枯竭的铀，目前的证据表明阈值降低至 免疫反应，导致免疫的某些臂的持续和增强活性 系统;一种最能描述为“免疫启动”的现象。此外，他们收到了20多个 可能使免疫系统超载的疫苗。为了支持这些考虑因素，主题与 GWVI经常显示出与自身免疫性疾病的常见病理特征，并普遍 炎症性疾病，例如促炎细胞因子的血浆浓度升高，非特异性 组织变性和器官衰竭。基于这个概念，三个提出的合作研究 旨在更好地了解启动免疫系统如何有助于GWVI-类型的项目。 通过探索在动物模型中概括的多个GWI条件如何协同和 最终为翻译研究提供了新的机械证据。例如，项目2被设计为 了解黄金周毒素如何诱导肠道炎性体激活会导致肠道营养不良，并可能导致 持续或增强的免疫炎症反应和GWVI符号。因为项目3的目标是 设计了一个假设，即缺乏特异性免疫会导致疫苗诱导的炎症反应 Brain，Project 2将与项目3合作，以测试炎性体启动和遗传的贡献 肠道营养不良和持续性免疫反应的多样性。同样，旨在的项目1 测试免疫学启动如何增强对心理压力源的炎症反应，将如何 通过探索NLRP3炎性症如何有助于与项目2和项目3合作 肠道营养不良或HLA多态性分别引起的输入增加。这些结果 研究引起了极大的兴趣 遗传多样性和肠道疾病的毒性反应，但它也将为测试新疗法提供见解 针对免疫治疗的持续激活的方法 抗疫苗毒素的方法，益生菌减弱肠道营养不良。我们提出的研究是创新的 就其范围而言，由于它将填补将来翻译研究所需的基本差距。最多 重要的是我们的多尺度技术创新方法，其中包括淘汰鼠模型 GWVI，包括HLA和NLRP3蛋白，将使我们的跨学科研究团队与 神经科学，药理学，微生物学，化学的杰出专业知识，以彻底研究 GWVI病因的基础分子机制。